Relative Contribution of Trypsin & Inflammation in Acute & Chronic Pancreatitis

胰蛋白酶的相对贡献

基本信息

批准号：
8304204
负责人：
ASHOK K SALUJA
金额：
$ 45.06万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): In the United States, more than 300,000 patients are admitted per year and over 2 billon dollars spent on their care. Despite the enormity of the disease, there is currently no targeted therapy, primarily due to incomplete understanding of pathophysiological mechanisms. The current paradigm of both acute and chronic pancreatitis revolves around intra-acinar activation of trypsin, which is believed to be central to both acinar cell injury and inflammation. However, evidence in support of the 'trypsin central' hypothesis can best be described as correlational and circumstantial. Thus far, no direct evidence exists to show that the premature activation of trypsinogen, observed early during pancreatitis, is casually responsible for the pathogenesis of acute pancreatitis. The exciting findings from our preliminary studies (using our newly developed cationic trypsinogen and cathepsin B knockout mice) aimed at elucidating the role of trypsin in pathogenesis of pancreatitis suggest that trypsin partially contributes to pancreatic injury in acute pancreatitis but is not required for development of chronic pancreatitis. This grant proposal is geared towards elucidating the actual contributions of intra-acinar activated trypsin and inflammatory pathways in acute and chronic pancreatitis and offers a unique opportunity to reconcile research of the last decades. In aim 1, we will evaluate the role of trypsin in pancreatic injury during acute pancreatitis using newly developed cationic trypsinogen knockout mice in several in vivo and in vitro models of the disease. In aim 2, we will study the role of inflammation in pancreatic and systemic injury during acute pancreatitis. This will involve use of cationic trypsinogen knockout mice in combination with mice harboring variants of NFkB signaling and creating mice with deletion of cationic trypsinogen and disrupted NFkB signaling. In aim 3, we will determine the role of trypsin in pathogenesis of chronic pancreatitis using two different models. In aim 4, the role of repeated inflammatory insult in the absence of trypsin activation will be investigated in chronic pancreatitis using cationic trypsinogen deleted and NFkB signaling defective mice. Successful completion of the proposed studies will uncover novel mechanisms for the pathogenesis of acute and chronic pancreatitis for which currently we do not have targeted therapeutics. A better understanding of the complex mechanisms will be useful for developing future novel treatments.

描述（由申请人提供）：在美国，每年有超过 300,000 名患者入院，治疗费用超过 20 亿美元。尽管这种疾病很严重，但目前还没有针对性的治疗方法，这主要是由于对病理生理机制的了解不完全。当前急性和慢性胰腺炎的模式都围绕腺泡内胰蛋白酶的激活，这被认为是腺泡细胞损伤和炎症的核心。然而，支持“胰蛋白酶中心”假说的证据最好被描述为相关性和环境性的。迄今为止，尚无直接证据表明胰腺炎早期观察到的胰蛋白酶原过早激活与急性胰腺炎的发病机制有关。我们的初步研究（使用我们新开发的阳离子胰蛋白酶原和组织蛋白酶 B 敲除小鼠）旨在阐明胰蛋白酶在胰腺炎发病机制中的作用，结果令人兴奋，表明胰蛋白酶部分导致急性胰腺炎的胰腺损伤，但不是慢性胰腺炎发展所必需的。胰腺炎。该拨款提案旨在阐明腺泡内激活的胰蛋白酶和炎症途径在急性和慢性胰腺炎中的实际贡献，并为协调过去几十年的研究提供了独特的机会。在目标 1 中，我们将使用新开发的阳离子胰蛋白酶原敲除小鼠在几种体内和体外疾病模型中评估胰蛋白酶在急性胰腺炎期间胰腺损伤中的作用。在目标 2 中，我们将研究炎症在急性胰腺炎期间胰腺和全身损伤中的作用。这将涉及使用阳离子胰蛋白酶原敲除小鼠与携带 NFkB 信号传导变异的小鼠相结合，并创建缺失阳离子胰蛋白酶原并破坏 NFkB 信号传导的小鼠。在目标 3 中，我们将使用两种不同的模型确定胰蛋白酶在慢性胰腺炎发病机制中的作用。在目标 4 中，将使用阳离子胰蛋白酶原缺失和 NFkB 信号传导缺陷的小鼠来研究慢性胰腺炎在没有胰蛋白酶激活的情况下重复炎症损伤的作用。成功完成拟议的研究将揭示急性和慢性胰腺炎发病机制的新机制，目前我们还没有针对性的治疗方法。更好地理解复杂机制将有助于开发未来的新疗法。